The biological underpinnings of Motoric Cognitive Risk syndrome: a multi-center study Motoric Cognitive Risk syndrome (MCR) is a recently described pre-dementia syndrome, characterized by the presence of subjective cognitive complaints and slow gait. MCR affects almost in 1 in 10 older adults, and has a high incidence in aging. MCR predicts risk of developing both Alzheimer?s disease (AD) and vascular dementia even after accounting for clinical overlap with Mild Cognitive Impairment syndrome (MCI). Unlike MCI, complex cognitive tests or assays are not required for diagnosing MCR, increasing its clinical utility. MCR has incremental predictive validity for dementia over its individual cognitive (cognitive complaints) and motoric (slow gait) components. While the epidemiology of MCR has been described, the biological underpinnings and neural substrates of MCR are not yet established. We draw together a multidisciplinary team to comprehensively conduct the first study to examine the pathogenesis of MCR syndrome. The MCR consortium includes an estimated 10,080 older individuals from 8 cohorts in USA, Canada, Europe, Asia and Australia. The MCR consortium has collaborated, shared and harmonized data, and published on MCR topics, establishing feasibility. Aim 1. Identify biological mechanisms underlying MCR incidence. Elevated peripheral inflammatory and oxidative stress biomarkers as well as single nucleotide polymorphisms in these pathways predicted incident MCR in our pilot studies. We will prospectively examine the role of inflammatory and oxidative stress biomarkers and explore genetic variants in these and related pathways in the pathogenesis of MCR. We will report associations in individual cohorts and as a second step in the pooled sample of 9,370 individuals in our MCR consortium with biomarker/genetic assays available or planned. Aim 2. Establish brain pathologies and substrates of MCR syndrome. Based on studies linking cerebral small vessel disease to cortical thinning, we hypothesize that cerebral small vessel disease (lacunar infarctions, cerebral microbleeds and white matter hyperintensities) may accelerate or incite gray matter loss that will clinically manifest as MCR. This aim will be prospectively tested using advanced imaging acquisition and analytical methods in individual cohorts and secondarily in the pooled sample of 3,100 individuals with neuroimaging. Aim 3. Compare and contrast biology and brain substrates for MCR and MCI syndromes. We will explore similarities and differences in new biological associations discovered in Aims 1 & 2 as well as known AD risk factors (APOE, hippocampal atrophy, etc.) with MCR and MCI. There is only partial clinical overlap between MCR and MCI. While we expect partial biological overlap, our studies show exclusive genetic predispositions, brain pathologies and brain substrates for MCR not seen with MCI. The MCR syndrome is not conceptualized as an alternate to MCI but complementary. Discovering unique biological associations of MCR may lead to new treatments that complement current MCI preventions. Our proposal is highly responsive to PAR-17-054: As per the PAR guidelines, we will use and/or harmonize existing data, collect new biological and imaging data not present in all cohorts, and add new participants as well as extend follow-up in 8 cohorts to clarify risk and protective factors for AD and related dementias via the MCR pathway. Our proposal also meets several action priorities of the National Alzheimer Plan such as accelerating efforts to identify early stages of AD, identifying biological mechanisms underlying dementia, expanding genetic epidemiology research to identify risk factors, and expanding international outreach to enhance collaboration.